Abstract
Previously identified as a breast and ovarian cancer susceptibility gene, BRCA1 has gained major scientific interest as a potential prognostic and/or predictive marker for various tumors, including non-small-cell lung cancer (NSCLC), the leading cause of cancer related mortality worldwide. BRCA1 plays a central role in DNA damage response (DDR. It undergoes phosphorylation by various DDR kinases at different serine residues, of which ser1524 is known to be specifically phosphorylated by ATM in response to genotoxic stress. We performed BRCA1 immunohistochemistry on several tissue microarrays (TMAs) of 113 early (I, II stage) and advanced (III, IV stage) NSCLCs, using MS110 antibody against the BRCA1 N-terminal and S1524 antibody against the phosphorylated form of BRCA1 protein at ser1524 (Abcam). Patients with III and IV stage disease were treated by adjuvant cisplatin-based chemotherapy. Staining results were correlated with overall survival (OS), disease free survival (DFS) and with the occurrence of brain metastases. BRCA1 S1524 nuclear positivity was significantly correlated with longer OS and DFS in stage I and II patients (P<0.05), while OS and DFS were shorter in S1524 positive stage III and IV patients (P<0.05). No significant correlation was found with brain metastases. The results show that BRCA1 phosphorylaton, at least in ser1524, differentiates the fate of early and advanced NSCLC as well as response to chemotherapy, but the underlying mechanisms are not completely understood. Detection of phosphorylated forms of BRCA1 might serve as a useful prognostic and predictive marker for patients with NSCLC.
Highlights
Non-small-cell lung cancer (NSCLC) is the leading cause of cancer related mortality and one of the major public health problems in the world
2 cases were positive in both – nucleus and cytoplasm and none of them in only the cytoplasm
BRCA1 S1524 antibody was positive in 27% of NSCLC cases, from which 11 cases were only nuclear, 13 – n/c and only one case showed cytoplasmic positivity
Summary
Non-small-cell lung cancer (NSCLC) is the leading cause of cancer related mortality and one of the major public health problems in the world. For patients with advanced and/or inoperable NSCLC, the most predictive indicators of survival after systemic chemotherapy are disease stage, performance status, and weight loss of more than 10% (ref.[4]). These factors are not sufficient for precise evaluation of individual patient prognosis and for predicting response after a given chemotherapy. Identified as a breast and ovarian cancer susceptibility gene, BRCA1 has gained major scientific interest as a potential prognostic and/or predictive marker for various tumors, including non-small-cell lung cancer (NSCLC), the leading cause of cancer related mortality worldwide. Detection of phosphorylated forms of BRCA1 might serve as a useful prognostic and predictive marker for patients with NSCLC
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